Stereochemistry and Intermolecular Interactions Influence Carrier Peptide-Mediated Insulin Delivery
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Stereochemistry and Intermolecular Interactions Influence Carrier Peptide-Mediated Insulin Delivery. / Diedrichsen, Ragna G.; Tuelung, Pernille S.; Foderà, Vito; Nielsen, Hanne M.
I: Molecular Pharmaceutics, Bind 20, Nr. 2, 2023, s. 1202–1212.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Stereochemistry and Intermolecular Interactions Influence Carrier Peptide-Mediated Insulin Delivery
AU - Diedrichsen, Ragna G.
AU - Tuelung, Pernille S.
AU - Foderà, Vito
AU - Nielsen, Hanne M.
N1 - Funding Information: This work was funded by the Novo Nordisk Foundation (Grand Challenge Programme: NNF16OC0021948). V.F. acknowledges VILLUM FONDEN for funding the project via the Villum Young Investigator grant “Protein Superstructures as Smart Biomaterials (ProSmart)” 2018–2023 (19175). The authors acknowledge the CPHSAXS (University of Copenhagen, Copenhagen, Denmark), funded by the Novo Nordisk Foundation (NNF19OC0055857). The authors acknowledge the CFIM (University of Copenhagen). The Shimadzu HPLC was funded by the Innovation Fund Denmark (grant no. 041-2010-3). The FLUOstar Omega plate reader was funded by the Innovative Medicines Initiative Joint Undertaking (grant no. 15363) from the European Union’s Seventh Framework Programme FP7/2007–2013 and EFPIA. The CLARIOstar Plus plate reader was funded by the VILLUM FONDEN (Young Investigator grant, project no. 19175). Laboratory coordinator Lene Grønne Pedersen (University of Copenhagen) is acknowledged for cell cultivation for the insulin permeation studies. The graphical abstract was created using icons from BioRender.
PY - 2023
Y1 - 2023
N2 - The inherent low oral bioavailability of therapeutic peptides can be enhanced by the cell-penetrating peptide penetratin and its analogues shuffle and penetramax applied as carriers for delivery of insulin. In this study, the objective was to gain mechanistic insights on the effect of the carrier peptide stereochemistry on their interactions with insulin and on insulin delivery. Insulin-carrier peptide interactions were investigated using small-angle X-ray scattering and cryogenic transmission electron microscopy, while the insulin and peptide stability and transepithelial insulin permeation were evaluated in the Caco-2 cell culture model along with the carrier peptide-induced effects on epithelial integrity and cellular metabolic activity. Interestingly, the insulin transepithelial permeation was influenced by the degree of insulin-carrier peptide complexation and depended on the stereochemistry of penetramax but not of penetratin and shuffle. The l-form of the peptides initially decreased the epithelial integrity comparable to that induced by the d-peptides, suggesting a comparable mechanism of action. The immediate decrease was reversible during exposure of the Caco-2 epithelium to the l-peptides but not during exposure to the d-peptides, likely a result of their higher stability. Overall, exploration of the stereochemistry showed to be an interesting strategy for carrier peptide-mediated insulin delivery.
AB - The inherent low oral bioavailability of therapeutic peptides can be enhanced by the cell-penetrating peptide penetratin and its analogues shuffle and penetramax applied as carriers for delivery of insulin. In this study, the objective was to gain mechanistic insights on the effect of the carrier peptide stereochemistry on their interactions with insulin and on insulin delivery. Insulin-carrier peptide interactions were investigated using small-angle X-ray scattering and cryogenic transmission electron microscopy, while the insulin and peptide stability and transepithelial insulin permeation were evaluated in the Caco-2 cell culture model along with the carrier peptide-induced effects on epithelial integrity and cellular metabolic activity. Interestingly, the insulin transepithelial permeation was influenced by the degree of insulin-carrier peptide complexation and depended on the stereochemistry of penetramax but not of penetratin and shuffle. The l-form of the peptides initially decreased the epithelial integrity comparable to that induced by the d-peptides, suggesting a comparable mechanism of action. The immediate decrease was reversible during exposure of the Caco-2 epithelium to the l-peptides but not during exposure to the d-peptides, likely a result of their higher stability. Overall, exploration of the stereochemistry showed to be an interesting strategy for carrier peptide-mediated insulin delivery.
KW - Caco-2 cell culture model
KW - cell-penetrating peptide
KW - mechanism of action
KW - real-time epithelial integrity
KW - stability
KW - transepithelial permeation
U2 - 10.1021/acs.molpharmaceut.2c00883
DO - 10.1021/acs.molpharmaceut.2c00883
M3 - Journal article
C2 - 36607603
AN - SCOPUS:85146004878
VL - 20
SP - 1202
EP - 1212
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 2
ER -
ID: 333700849